The present invention provides apparatus for measuring the electrical impedance of a tissue sample.
It is known that certain medical conditions can be monitored by measuring the impedance of a patient's tissue. This can be done by applying electrodes to the tissue through which a low voltage current can be passed through the tissue. It is known to use this technique to detect abnormal cell growth which can be indicative of a tumour. Electrical impedance spectroscopy has been used to identify premalignant changes in tissue samples, especially to identify the pre-cancerous phase of cervical cancer, known as cervical intraepithelial neoplasia (CIN).
Impedance measurements can be used to detect other conditions of a patient. For example, onset of labour is accompanied by changes in tissue impedance which can be identified by such measurements.
Electrical impedance spectroscopy measures the electrical impedance spectra of superficial tissues, such as for example cervical epithelium by placing an electrically conductive probe in contact with the tissue sample. Biological tissues have an electrical impedance which is dependant on the frequency of the current passed through the tissue. The biological tissues contain a number of components, such as a nucleus and a cytoplasm which have both resistive and capacitive properties. It is known that in cancerous and pre-cancerous tissues there is a significant change in the size of the cell nuclei, in the shape of the cells and in the arrangement of cells which form the tissue. These changes affect the electrical impedance of the tissue sample and therefore electrical impedance tomography can be used to detect significant changes in cell structure and therefore diagnose patients suffering from CIN.
The magnitude of the electrical impedance and the dependence of the electrical impedance on frequency of a tissue sample have been found to be indicative of the tissue composition. It has been found that different tissue structures are associated with different frequency bands within an electrical impedance spectrum.
It has been found that at low frequencies (less than about 1 kHz) the current is unable to pass through the cells due to the capacitance of the cellular membrane and charge accumulation occurs at large membrane interfaces. At intermediate frequencies, such as in the region of about 1 kHz to 1 MHz (also known as the β dispersion region) cell structures are the main determinant of tissue electrical impedance and current begins to penetrate the cell membranes. However, at higher frequencies (greater than about 1 MHz) the current is able to pass through the cells and the nuclei and at even higher frequencies (>1 GHz) the molecular structure is the determining factor contributing towards the electrical impedance of the tissue sample.
Within the lower part of the β dispersion range, low frequency current can be considered to be passing through the extracellular space within the tissue sample. The current passes around the cells and the resistance to the flow of the current will therefore depend upon the cell spacings and how the cells are arranged. At higher frequencies however current can penetrate the cell membranes and pass through both the intracellular and extracellular spaces. The current will therefore pass into the cells and the resistance to current flow will be determined by intracellular volume and possibly the size of the nucleus.
It is known that by measuring the electrical current patterns produced by a tissue sample over a range of frequencies, and applying an inverse modelling procedure, electrical parameters resulting from the tissue structure may be determined. The intracellular resistance of a given tissue sample has been found to be significantly affected by the relative sizes of the nucleus and the cell. It has therefore been found that the electrical impedance of tissue samples can be used to distinguish between tissues having different nuclear volume to cytoplasm volume ratios. Tissue samples having a higher ratio of nuclear volume to cytoplasm volume may be indicative of pre-cancerous tissues. The application of electrical impedance measurements using a probe which bears four electrodes on an end face in cervical cytology is disclosed in Electronics Letters, 36 (25) 2060-2062 and in The Lancet, 355: 892-95.
For example, it is known that in cervical tissues the major changes in the pre-cancerous stages are the gradual breakdown of superficial cell layering and the increase in the size of the cell nuclei. These changes will therefore have an effect on the electrical impedance of a tissue sample at intermediate frequencies and therefore electrical impedance can be used to diagnose the presence of pre-cancerous tissues.
The electrical impedance of a tissue sample is measured to give mean values of electrical impedance at a number of frequencies. This data, forming an electrical impedance spectrum, is then fitted by a least square deviation method to a Cole equation as discussed in US-2003/0105411 of the form:
  Z  =            R      ∞        +                  (                              R            0                    -                      R            ∞                          )                    (                  1          +                                    (                              jF                /                                  F                  c                                            )                                      (                              1                -                α                            )                                          to give estimates of R0, R∞ and Fc. R0 and R∞ are the electrical impedances of the tissue sample at very low and very high frequencies respectively, Fc is a frequency and α is a constant. α increases with the inhomogeneity of the tissue however it can be assumed that α is zero to improve the accuracy in the estimation of Fc. In this case an equivalent electrical circuit consisting of a resistor R placed in parallel with a resistor S and capacitor C in series will have an impedance Z, given by the above equation, where:
            R      0        =    R    ,            R      ∞        =          RS              R        +        S              ,            F      c        =          1              2        ⁢        π        ⁢                                  ⁢                  C          ⁡                      (                          R              +              S                        )                              
Parameters R, S and C can therefore be determined from the fitted Cole equation. Because the probe was calibrated in saline of known conductivity, R and S are inversely proportional to conductivity and have the units of Ωm. R and S can therefore be related to the extracellular and intracellular spaces respectively. C is related to the cell membrane capacitance and is given in units of μF·m−1.
WO-01/67098 discloses the use of an electrically conductive probe for measuring the electrical impedance of tissue samples comprising a tetrapolar electrode arrangement positioned at the probe tip for the in vivo measurement of the electrical impedance spectra of a tissue sample. Subject matter disclosed in that document is incorporated in the specification of the present application by this reference.